Targeting MAP2K1 mutation with trametinib in a triple wild-type melanoma patient.

Abstract

e21027 Background: MAP2K1 inhibitors combined with BRAF inhibitors provide a prolonged progression-free survival for BRAF mutant patients. However, the impact of MEK inhibition of MAP2K1 mutant and BRAF/NRAS/NF1 wild type melanoma patients remains elusive. Methods: We performed next-generation sequencing using an in-house developed 400 full exon panel for one of our triple wild type (BRAF/NRAS/NF1) melanoma patient. The patient received off-label, trametinib at a dose of 2 mg o.d. We performed additional sequencing at progression. After progression, the patient was treated off-label with combined trametinib and palbociclib therapy. Furthermore, we screened the TCGA melanoma and MSK-IMPAKT databases for patients with similar mutation profiles. Results: Our patient presented with dual somatic MAP2K1 mutations at Cys121Ser and Pro124Arg with a 68% allele frequency. The tumor also harbored a minor EGFR mutant clone (11% allele frequency) and a complete loss of the CDKN2A locus. The patient received trametinib and after two months presented a partial response as per RECIST1.1. However, after two additional months, the patient progressed. A new biopsy was performed, and the treatment was modified to combine trametinib and palbociclib to co-target MAP2K1 and the loss of the CKDN2A locus. The patient progressed under dual trametinib/palbociclib therapy without any objective benefit. The on-progression biopsy showed the absence of a gatekeeper mutation of MAP2K1 and the persistence of the loss of the CDKN2A locus. We detected a large number of novel copy number variations, most notable amplification of MITF (9x), FGFR1 (10X) and of MDM2 (16x). We also detected a loss of the minor, EGFR mutant clone. The analysis of large-scale state transitions (LSTs) for deficiency in homolog recombination (HRDness) was negative in pre and post-treatment biopsies. Conclusions: Our patient provides unique evidence to target solitary MAP2K1 mutations in triple wild melanoma by MEK1 inhibitors. Resistance to MEK1 inhibition developed rapidly and likely involved FGFR1 and MDM2, which have not been previously associated with resistance to MEK inhibitor monotherapy. The addition of palbociclib could not rescue these potential resistance mechanisms.